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In silico analysis of the effects of disease-associated mutations of β-hexosaminidase A in Tay‒Sachs disease

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Abstract

Tay‒Sachs disease (TSD), a deficiency of β-hexosaminidase A (Hex A), is a rare but debilitating hereditary metabolic disorder. Symptoms include extensive neurodegeneration and often result in death in infancy. We report an in silico study of 42 Hex A variants associated with the disease. Variants were separated into three groups according to the age of onset: infantile (n=28), juvenile (n=9) and adult (n=5). Protein stability, aggregation potential and the degree of conservation of residues were predicted using a range of in silico tools. We explored the relationship between these properties and the age of onset of TSD. There was no significant relationship between protein stability and disease severity or between protein aggregation and disease severity. Infantile TSD had a significantly higher mean conservation score than nondisease associated variants. This was not seen in either juvenile or adult TSD. This study has established that the degree of residue conservation may be predictive of infantile TSD. It is possible that these more highly conserved residues are involved in trafficking of the protein to the lysosome. In addition, we developed and validated software tools to automate the process of in silico analysis of proteins involved in inherited metabolic diseases. Further work is required to identify the function of well-conserved residues to establish an in silico predictive model of TSD severity.

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Acknowledgements

RK was supported by a summer studentship funded by Queen’s University, Belfast. This research did not receive any other specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

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Authors and Affiliations

  1. Brighton and Sussex Medical School, University of Sussex, Falmer, Brighton, BN1 9PX, UK

    Mohammad Ihsan Fazal

  2. School of Biological Sciences, Queen’s University Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, BT9 7BL, UK

    Rafal Kacprzyk

  3. School of Pharmacy and Biomolecular Sciences, University of Brighton, Huxley Building, Lewes Road, Brighton, BN2 4GJ, UK

    David J. Timson

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  1. Mohammad Ihsan Fazal
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  2. Rafal Kacprzyk
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  3. David J. Timson
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Correspondence to David J. Timson.

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Fazal, M.I., Kacprzyk, R. & Timson, D.J. In silico analysis of the effects of disease-associated mutations of β-hexosaminidase A in Tay‒Sachs disease. J Genet 99, 42 (2020). https://doi.org/10.1007/s12041-020-01208-8

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  • DOI: https://doi.org/10.1007/s12041-020-01208-8

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